Despite a seemingly infinite amount of reactions that involve carbon-containing compounds, the vast majority can be divided into one of two large groups: reactions in which a carbon atom undergoes oxidation state change, and reactions in which its oxidation state remains unaffected. Each oxidation state of carbon has a set of reactions associated with it. A subset of reactions relevant to carbon-nitrogen bond formation illustrates this point (Scheme 1). For instance, primary alcohols can undergo nucleophilic displacement to generate amines, enolizable aldehydes can condense with amines giving enamines, whereas carboxylic acids can be converted into amides.

Chemical synthesis of targets of varied complexity is an exercise in interspersing non-redox reactions with the carbon oxidation state adjustments. Chemoselectivity, defined as the preferential reaction of a chemical reagent with one of two or more different functional groups, is one of the biggest challenges facing chemical synthesis (IUPAC Compendium of Chemical Terminology, 2nd ed., 1997). Avoiding the problems of chemoselectivity using protecting groups is commonplace, but comes at the expense of atom (B. M. Trost, Science 1991, 254, 1471) and step economy (P. A. Wender, M. P. Croatt, B. Witulski, Tetrahedron 2006, 62, 7505). In this regard, it is instructive to observe that biosynthesis avoids the chemoselectivity problems by molecular shape recognition (R. Hili, A. K. Yudin, Nat. Chem. Biol. 2006, 2, 284). The event of binding into an enzyme active site allows precise positioning of the functional group about to undergo transformation. In comparison, very few synthetic reagents obey the Michaelis—Menten kinetics. Instead, electronic and/or steric requirements of different functional groups present in a given reactant have to be taken into account in order to reach high levels of selectivity. Parameters such as pKa, redox potential, and A values, are common metrics used by organic chemists in order to compare and predict reactivity of different molecules. None of these parameters come close to describing the overall property of a given molecule. In contrast, enzymatic systems are holistic in their approach to chemical transformations.
In order to find general solutions to protecting group-free synthesis, one approach is to develop reagents and catalysts that emulate enzymatic efficiency with regard to chemoselectivity and practical turnover numbers (For recent discussions, see: R. W. Hoffman, Synthesis 2006, 3531; P. S. Baran, T. J. Maimone, J. M. Richter, Nature 2007, 446, 404). On the other hand, new ideas about interrelationships between functional groups are expected to play a significant role.
In an ideal world, one would have a capability to chemoselectively manipulate molecules equipped with mutually reactive functional groups. In the realm of acid/base chemistry, the so-called amphoteric molecules have been known for some time. The term amphoteric is of Greek origin: amphoteros literally means “both of two” (Zell's popular encyclopedia; a universal dictionary of English language, science, literature and art by L. Colage, Philadelphia, T. E. Zell, 1871). Although the origin of the word is not related to any particular chemical property, this term has been mainly used in order to refer to a molecule that can act as both acid and base.
For instance, amino acids are amphoteric compounds, characterized by an isoelectric point at which the molecule exists in its zwitterionic state (e.g. L-serine in FIG. 1). Depending on pH, the position of proton can change, affecting the chemical behaviour of the amino acid. Accordingly, amphoterism has belonged to the domain of thermodynamics since proton transfer is typically diffusion-limited. The thermodynamics of proton transfer can temporarily stabilize unstable molecules that contain nucleophilic and electrophilic centres. Fischer, who in 1908 prepared glycinal from the reduction of its ester, demonstrated that protection of the amine functional group by proton at acidic pH stabilized the amino aldehyde, albeit briefly (E. Fischer, Chem. Ber. 1908, 41, 1019). More recently, Myers and co-workers have used a similar method of amine protonation to establish the epimerization-free adduct formation between amino aldehydes with nucleophilic solvent molecules (A. G. Myers, D. W. Kung, B. Zhong, J. Am. Chem. Soc. 2000, 122, 3236). When the pH of the medium was increased to value greater than 5, the amino aldehydes decomposed through self-condensation reactions. The possibility of self-condensation can be suppressed, but it requires incorporation of a quaternary α-carbon (Ooi, T.; Saito, A.; Maruoka, J. J. Am. Chem. Soc. 2003, 125, 3220).
There are few examples of synthetically useful molecules one can consider amphoteric based on kinetic grounds. The most mechanistically instructive case is that of the isocyanide (FIG. 1), first synthesized in 1859 (W. Lieke, Justus Liebigs Ann. Chem. 1859, 112, 316). Two of the widely used multicomponent reactions owe their efficiency to the amphoteric nature of the isocyanide. The Passerini reaction involves a three component condensation between an isocyanide, an aldehyde, and a carboxylic acid to generate α-acyloxycarboxamides. By introducing another component—an amine—into the reaction, Ugi developed a four-component process, which is used to generate dipeptides and other valuable molecules (I. Ugi, A. Dömling, Angew. Chem. 2000, 112, 3300; Angew. Chem. Int. Ed. 2000, 39, 3168; Multicomponent Reactions (Eds.: J. Zhu, H. Bienaymé), Wiley, N.Y., 2005). The critical mechanistic point of this reaction is that the isocyanide carbon establishes a connection with both nucleophile (carboxylic acid) and electrophile (imine) (Scheme 2). The unique amphoteric nature of the isocyanide carbon centre facilitates the discovery of multicomponent processes using simple building blocks (L. Weber, K. Illgen, M. Almstetter, Synlett 1999, 161).

Continuing interest in stereochemically complex natural products and natural product-inspired synthetic molecules requires processes that minimize protection/deprotection sequences on incompatible functional groups. Identification of such reactions, especially in complex heterocycle synthesis, facilitates discovery of bioactive molecules.
Carbonyl groups are arguably the most synthetically useful oxidation state of carbon (Scheme 1) since condensations between amines and carbonyl groups give rise to enamines, some of the most widely used synthetic intermediates (The Chemistry of Enamines (Ed.: Z. Rappoport), New York, 1994). Besides their utility as building blocks in target-oriented synthesis, enamines have many other important applications. For instance, many developments in an active area of current research, organocatalysis, depend on enamine generation for catalytic turnover (B. List, Chem. Commun. 2006, 819; G. Lelais, D. W. C. Macmillan, Aldrichimica Acta 2006, 39, 79). Ironically, in the context of synthesis, enamine formation can be regarded as a limitation: due to their inherent reactivity, a secondary amine and an aldehyde or a ketone cannot be carried through a synthetic sequence in their unprotected forms. Unveiling a secondary amine in the presence of an aldehyde or a ketone is done when an instant condensation resulting in an iminium/enamine system is desired (Scheme 3). It is easy to see that if the unprotected derivatives were to have a kinetic barrier against condensation, they would afford a number of strategic as well as tactical advantages.

It is difficult to see how an unprotected secondary amine could coexist with an aldehyde in the same molecule for a prolonged period of time (for reviews on N-protected amino aldehydes see: Jurczak, J.; Golebiowski, A. Chem. Rev. 1989, 89, 149; Reetz, M. T. Anew. Chem. Int Ed. 1991, 30, 1531; Sardina, F. J.; Rapoport, H. Chem. Rev. 1996, 1825; D-Glucosamine, a naturally occurring amino aldehyde, is stable as a cyclic aminal salt: Fischer, E.; Leuchs, H. Ber. Dtsch. Chem. Ges. 1902, 36, 24; glycinal was characterized through degradation studies: Fischer, E. Ber. 1908, 41, 956; Fischer, E. Ber. 1908, 41, 1019; for a preparation of histidinal dihydrochloride, see: Adams, E. J. Biol. Chem. 1955, 217, 317).
Rheinhoudt (Rheinhoudt et al. Journal of Organic Chemistry 1983, 48(4), 486) has previously reported an unprotected aziridine aldehyde (compound 9, see Scheme III from this paper and Scheme 4 shown below).

However, this aziridine aldehyde was isolated as a by-product during a low-yielding synthesis of target compound 14a, and could not be obtained in pure form due to its instability.
Thus, in view of the foregoing, there remains a need for the development of synthetic molecules for use in processes that minimize protection/deprotection sequences on incompatible functional groups, such as amines and aldehydes.
Reversible protease inhibitors feature prominently among modern therapeutic agents (Babine, R. E.; Bender, S. L. Chem. Rev. 1997, 97, 1359). The so-called reduced amide bond isosteres contain aminomethylene functional groups in place of the selected amide linkages (Scheme 5a below). This structural substitution is present in a wide range of aspartyl protease inhibitors (Maly, D. J., Huang, L., Ellman, J. A. ChemBioChem. 2002, 3, 17; Leung, D.; Abbenante, G.; Fairlie, D. P. J. Med. Chem. 2000, 43, 305). The aminomethylene fragment is isosteric with the tetrahedral transition state formed during amide hydrolysis. This ensures that the peptidomimetic inhibitor binds to the protease target tighter than the substrate. At the same time, the reduced amide bond analog is not cleaved by the protease and often displays better binding than its peptide prototype (Szelke, M.; Leckie, B.; Hallett, A.; Jones, D. M.; Sueiras, J.; Atrash, B.; Lever, A. F. Nature 1982, 299, 555). Many different modes of binding between proteases and their inhibitors have been observed by X-ray crystallography (Wlodawer, A.; Erickson, J. Annu. Rev. Biochem. 1993, 62, 543). The diversity of recognition mechanisms underscores the importance of optimizing the peptidomimetic inhibitor/protease interactions in the vicinity of the active site.
The most widely employed strategy towards reduced amide bond isosteres is based on N-protected amino aldehydes (Scheme 5b) (Gryko, D.; Chalko, J.; Jurczak, J. Chirality 2003, 15, 514). Typically, a peptide or a nitrogen-protected amino acid (“NHP”) is converted into the corresponding aldehyde by first forming an ester or a Weinreb amide, which is subsequently reduced by a hydride transfer reagent. These steps are followed by reductive amination with an appropriate amine component.

Although this valuable reaction sequence has been used in numerous academic and industrial applications, there are significant challenges that face this chemistry. The amino aldehydes as well as their immediate precursors are notoriously sensitive to epimerization (Potetinova, J. V.; Milgotina, E. I.; Makarov, V. A.; Voyushina, T. L. Russ. J. Bioorg. Chem. 2001, 27, 141). In addition, the imine/enamine equilibrium triggered during the reductive amination can lead to further epimerization on both the amine- and the aldehyde sides of the peptidomimetic fragment (Scheme 5b). Epimerizations on both the amine and the aldehyde sides during peptidomimetic synthesis have been documented (Aurelio, L.; Brownlee Robert, T. C.; Hughes Andrew, B. Chem. Rev. 2004, 104, 5823; Wasserman, H. H.; Berger, G. D.; Cho, K. R. Tetrahedron Lett. 1982, 23, 465; Jensen, K. J.; Alsina, J.; Songster, M. F.; Vagner, J.; Albericio, F.; Barany, G. J. Am. Chem. Soc. 1998, 120, 5441; Giannis, A.; Kolter, T. Angew. Chem. Int. Ed. 1993, 32, 1244; Ho, P. T.; Chang, D.; Zhong, J. W. X.; Musso, G. F. Peptide Res. 1993, 6, 10). Last but not least, reliance on protecting groups at nitrogen in amino aldehydes diminishes the synthetic efficiency of these operations.
Thus, there is a need for new strategies for developing peptidomimetics.